Novel GAA mutations in patients with Pompe disease

Turaça, Lauro Thiago; Faria, Douglas Oliveira Soares de; Kyosen, Sandra Obikawa; Teixeira, Valber Dias; Motta, Fabiana Louise; Pessoa, Juliana Gilbert; Silva, Marina Rodrigues e; Almeida, Sandro Soares de; D’Almeida, Vânia; Rojas, María Verónica Muñoz; Martins, Ana María; Pesquero, João Bosco

doi:10.1016/j.gene.2015.02.023

Cited by 20 publications

(13 citation statements)

References 72 publications

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“…Our finding, and the fact that an individual homozygous for the pseudo deficiency allele was already reported in Brazil (Turaça et al, 2015) suggests that this allele is present in our population. This report of GAA pseudo deficiency detected by newborn screening illustrates and reinforces the need that such programs have a comprehensive protocol including further biochemical and genetic analysis, to provide a final diagnosis to the cases who had a positive result in the initial screening test.…”

Section: Resultssupporting

confidence: 72%

Research Article Pseudo deficiency of acid α-glucosidase: a challenge in the newborn screening for Pompe diseases

MÃ¡laga¹,

Brusius-Facchin²,

Michelin‐Tirelli³

et al. 2017

Genet. Mol. Res.

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When a low activity of acid α-glucosidase (GAA) is found, particularly in newborn screening programs, to differentiate α-glucosidase pseudo deficiency from true Pompe disease is important and urgent, as the result generates parental stress and also because this differentiation drives decisions related to the management of the case. Here, we report a case of GAA pseudo deficiency detected in a newborn screening performed by a private laboratory in Brazil. The confirmatory laboratory investigation performed at our service showed reduction of GAA activity on the dried blood spot, with inconclusive results when GAA activity was assayed in leukocytes. Genotyping of the GAA gene with nextgeneration sequencing revealed the common pathogenic mutation c.-32-13T>G and the "pseudo deficiency allele" p. [Gly576Ser; Glu689Lys], each one in heterozygous state and in trans. This report illustrates the need of newborn screening programs to have the adequate support to perform a comprehensive investigation whenever an abnormality is found in the initial screening test.

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Section: Resultssupporting

confidence: 72%

Research Article Pseudo deficiency of acid α-glucosidase: a challenge in the newborn screening for Pompe diseases

MÃ¡laga¹,

Brusius-Facchin²,

Michelin‐Tirelli³

et al. 2017

Genet. Mol. Res.

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“…Mutational analysis revealed a high prevalence of the intronic mutation IVS1-13T>G. Patients homozygous for this mutation had normal biochemical tests for serum CPK, ALT, AST and urinary Glc4 excretion. In two patients who were compound heterozygous for IVS1-13T>G and the frameshift mutation p.P79RfsX12 that is associated with a very severe phenotype [26,27], CPK was elevated and Glc4 showed increased values without cardiac involvement. False-positive newborns were carriers for a single allelic pathogenic mutation, pseudodeficiency alleles or a variant of unknown significance.…”

Section: Resultsmentioning

confidence: 97%

Implementation of Second-Tier Tests in Newborn Screening for Lysosomal Disorders in North Eastern Italy

Burlina

Polo

Rubert

et al. 2019

IJNS

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The increasing availability of treatments and the importance of early intervention have stimulated interest in newborn screening for lysosomal storage diseases. Since 2015, 112,446 newborns in North Eastern Italy have been screened for four lysosomal disorders—mucopolysaccharidosis type I and Pompe, Fabry and Gaucher diseases—using a multiplexed tandem mass spectrometry (MS/MS) assay system. We recalled 138 neonates (0.12%) for collection of a second dried blood spot. Low activity was confirmed in 62 (0.06%), who underwent confirmatory testing. Twenty-five neonates (0.02%) were true positive: eight with Pompe disease; seven with Gaucher disease; eight with Fabry disease; and two with Mucopolysaccharidosis type I. The combined incidence of the four disorders was 1 in 4497 births. Except for Pompe disease, a second-tier test was implemented. We conclude that newborn screening for multiple lysosomal storage diseases combined with a second-tier test can largely eliminate false-positives and achieve rapid diagnosis.

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“…Blood samples were collected from peripheral veins in heparin-coated vacuum tubes, and the blood was immediately spotted onto filter paper (Whatman ® 903). The GAA enzyme activity in the DBS was assayed according to standard procedures adapted from the method described by Chamoles et al 13 apud Müller et al 12 and Turaça et al 14…”

Section: Methodsmentioning

confidence: 99%

“…Genetic analysis confirmed two pathogenic variants in the GAA gene in our patient. The mutation c.-32-13T>G is by far the most frequent worldwide pathogenic variant in the GAA gene and the R854X is a well-documented African-American mutation 8,10,14,20 . Both mutations were previously reported in association with PD in Brazilian patients 14,20 .…”

Section: A B Cmentioning

confidence: 99%

“…Recently, some studies have proposed using next generation sequencing to screening PD in patients with limb-girdle muscular weakness as it is faster and more cost-effective than Sanger sequencing 2,14 . Although more studies need to be performed to establish its place in the investigation of LOPD, next generation sequencing has the advantage of diagnosing other causes of limb-girdle muscular weakness as well.…”

Section: A B Cmentioning

confidence: 99%

See 1 more Smart Citation

Late-onset Pompe disease: what is the prevalence of limb-girdle muscular weakness presentation?

Lorenzoni

Kay

Higashi

et al. 2018

Arq. Neuro-Psiquiatr.

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Pompe disease is an inherited disease caused by acid alpha-glucosidase (GAA) deficiency. A single center observational study aimed at assessing the prevalence of late-onset Pompe disease in a high-risk Brazilian population, using the dried blood spot test to detect GAA deficiency as a main screening tool. Dried blood spots were collected for GAA activity assay from 24 patients with "unexplained" limb-girdle muscular weakness without vacuolar myopathy in their muscle biopsy. Samples with reduced enzyme activity were also investigated for GAA gene mutations. Of the 24 patients with dried blood spots, one patient (4.2%) showed low GAA enzyme activity (NaG/AaGIA: 40.42; %INH: 87.22%). In this patient, genetic analysis confirmed two heterozygous mutations in the GAA gene (c.-32-13T>G/p.Arg854Ter). Our data confirm that clinicians should look for late-onset Pompe disease in patients whose clinical manifestation is an "unexplained" limb-girdle weakness even without vacuolar myopathy in muscle biopsy.

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Novel GAA mutations in patients with Pompe disease

Cited by 20 publications

References 72 publications

Research Article Pseudo deficiency of acid α-glucosidase: a challenge in the newborn screening for Pompe diseases

Research Article Pseudo deficiency of acid α-glucosidase: a challenge in the newborn screening for Pompe diseases

Implementation of Second-Tier Tests in Newborn Screening for Lysosomal Disorders in North Eastern Italy

Late-onset Pompe disease: what is the prevalence of limb-girdle muscular weakness presentation?

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